EPILEPSY | +50 articles

[mr peabody]

Anti-seizure mechanism of cilantro uncovered

Neuroscience News | July 22, 2019

In a new study, researchers uncovered the molecular action that enables cilantro to effectively delay epileptic seizures.

The study, published in FASEB Journal, explains the molecular action of cilantro as a highly potent KCNQ channel activator. This new understanding may lead to improvements in therapeutics and the development of more effective drugs.

“We discovered that cilantro, which has been used as a traditional anticonvulsant medicine, activates a class of potassium channels in the brain to reduce seizure activity,” said Geoff Abbott, Ph.D., professor of physiology and biophysics at the UCI School of Medicine and principal investigator on the study. “Specifically, we found one component of cilantro, called dodecenal, binds to a specific part of the potassium channels to open them, reducing cellular excitability. This specific discovery is important as it may lead to more effective use of cilantro as an anticonvulsant, or to modifications of dodecenal to develop safer and more effective anticonvulsant drugs.”

Researchers screened cilantro leaf metabolites, revealing that one – the long-chain fatty aldehyde (E)-2-dodecenal – activates multiple potassium channels including the predominant neuronal isoform and the predominant cardiac isoform, which are responsible for regulating electrical activity in the brain and heart. This metabolite was also found to recapitulate the anticonvulsant action of cilantro, delaying certain chemically-induced seizures. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important potassium channels.

Documented use of botanical folk medicines stretches back as far as recorded human history. There is DNA evidence, dating back 48,000 years, that suggests the consumption of plants for medicinal use by Homo neanderthalensis. Archaeological evidence, dating back 800,000 years, suggests a non-food use of plants by Homo erectus or similar species. Today, evidence of the efficacy of botanical folk medicines ranges from anecdotal to clinical trials. In many cases, these “medicines” are currently consumed, often on a large scale, as foodstuffs or food flavoring. Cilantro, known as coriander in the UK, is one example. Cilantro has been consumed by human beings for at least 8,000 years. It was found in the tomb of Tutankhamen and is thought to have been cultivated by the ancient Egyptians.

“In addition to the anticonvulsant properties, cilantro also has reported anti-cancer, anti-inflammatory, anti-fungal, antibacterial, cardioprotective, gastric health and analgesic effects,” said Abbott. “And, the best part is it tastes good!”

Anticonvulsant mechanism of cilantro uncovered - Neuroscience News

Study reveals a molecular action that enables cilantro to effectively delay seizures. One component of cilantro, dodecenal, binds to a specific part of the potassium channel to open them, reducing cellular excitability.

neurosciencenews.com

 

[mr peabody]

CBD significantly reduces seizures in patients with severe form of epilepsy

Science Daily | NYU Langone Health | Apr 9 2019

CBD, a compound derived from the cannabis plant that does not produce a "high" and has been an increasing focus of medical research, was shown in a new large-scale, randomized, controlled trial to significantly reduce the number of dangerous seizures in patients with a severe form of epilepsy called Lennox-Gastaut syndrome.

In the new study comparing two doses of CBD to a placebo, the researchers reported a 42 percent reduction in "drop seizures" -- a type of seizure that results in severe loss of muscle control and balance -- in patients taking a 20 mg/kg/d CBD regimen, a 37 percent reduction in those on a 10 mg/kg/d CBD regimen, and a 17 percent reduction in a group given a placebo.

The phase III trial was led by principal investigator and study first co-author Orrin Devinsky, MD, a professor of neurology, neurosurgery, and psychiatry at NYU School of Medicine and director of NYU Langone's Comprehensive Epilepsy Center, and was published in The New England Journal of Medicine.

"This new study adds rigorous evidence of cannabidiol's effectiveness in reducing seizure burden in a severe form of epilepsy and, importantly, is the first study of its kind to offer more information on proper dosing," says Dr. Devinsky. "These are real medications with real side effects, and as providers we need to know all we can about a potential treatment in order to provide safe and effective care to our patients."

The study included an investigational liquid, oral formulation of CBD called Epidiolex. The product is manufactured by GW Pharmaceuticals, which operates in the U.S. as Greenwich Biosciences; GW Pharmaceuticals funded the clinical trial.

Safety of two CBD doses studied

Lennox-Gastaut syndrome is a rare and severe form of epilepsy characterized by frequent drop seizures and severe cognitive impairment. Six medications are approved to treat seizures in patients with the syndrome, but disabling seizures occur in most patients despite these treatments.

Researchers enrolled 225 patients (age 2 to 55) with Lennox-Gastaut syndrome across 30 international sites in a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of two doses of CBD: Seventy-six patients received 20 mg/kg/d CBD, 73 received 10 mg/kg/d CBD, and 76 were given a placebo. All medications were divided into two doses per day for 14 weeks. The number of seizures were monitored beginning four weeks prior to the study for baseline assessment, then tracked throughout the 14-week study period and afterwards for a four-week safety check.

Side effects occurred in 94 per of patients in the 20 mg CBD group, 84 percent in the 10 mg CBD group, and 72 percent of those taking placebo. Side effects were generally reported as mild or moderate in severity and those that occurred in more than 10 percent of patients included: sleepiness, decreased appetite, diarrhea, upper respiratory infection, fever, vomiting, nasopharyngitis, and status epilepticus. Fourteen patients taking CBD experienced dose-related, elevated liver enzymes that were reversible. Seven participants from the CBD group withdrew from the trial due to side effects compared to one participant in the placebo group.

"This landmark study provides data and evidence that Epidiolex can be an effective and safe treatment for seizures seen in patients with Lennox Gastaut Syndrome, a very difficult to control epilepsy syndrome," adds study co-first author, Anup Patel, MD, chief of Neurology at Nationwide Children's Hospital.

A study led by Dr. Devinsky published in last May's New England Journal of Medicine showed a 39 percent drop in seizure frequency in patients with a different rare form of epilepsy, Dravet syndrome. Those findings represented the first large-scale, randomized clinical trial for the compound. Open label CBD studies led by Dr. Devinsky also have shown positive results for treatment-resistant epilepsies.

In April, a U.S. Food and Drug Administration advisory panel unanimously voted to recommend approval of a new drug application for Epidiolex cannabidiol oral solution, following a meeting where researchers, including Dr. Devinsky, presented their findings. The FDA will decide whether to approve the medication in late June.

"While the news gives hope for a new treatment option to the epilepsy community, more research remains imperative to better determine the effects of CBD and other similar cannabis-derived compounds on other forms of the disease and in more dosing regimens," says Dr. Devinsky.

http://www.avstim.com/news-1/2019/4/9/cannabidiol-significantly-reduces-seizures-in-patients-with-severe-form-of-epilepsy

 

[mr peabody]

Nicklaus Children’s Hospital

CBD may reduce seizures for children with difficult-to-treat epilepsy

Neuroscience News | May 1, 2019

Taking a pharmaceutical formulation of cannabidiol, a cannabis-based medicine, cut seizures nearly in half for children with a rare and severe type of epilepsy called Dravet syndrome, according to a phase 3 study released today, to be presented at the American Academy of Neurology’s 71st Annual Meeting in Philadelphia. Dravet syndrome, which starts in infancy, can lead to intellectual disability and frequent, prolonged seizures. Cannabidiol is derived from marijuana that does not include the psychoactive part of the plant that creates a “high.”

“It’s exciting to be able to offer another alternative for children with this debilitating form of epilepsy and their families,” said study author Ian Miller, MD, of Nicklaus Children’s Hospital, formerly Miami Children’s Hospital, in Florida. “The children in this study had already tried an average of four epilepsy drugs with no success and at the time were taking an average of three additional drugs, so to have this measure of success with cannabidiol is a major victory.”

The study involved 199 children with an average age of 9 who were divided into three groups. One group received 20 milligrams per kilogram (mg/kg) per day of cannabidiol, the second group received 10 mg/kg per day and the third group received a placebo.

Seizures were recorded for four weeks before the treatments were started to establish a baseline. Then the participants received the treatment for 14 weeks. By the end of the study, seizures with convulsions had decreased for those taking the high dose of the drug by 46 percent and by 49 percent for those taking the lower dose of the drug, compared to 27 percent for those taking the placebo.

The study involved 199 children with an average age of 9 who were divided into three groups. One group received 20 milligrams per kilogram (mg/kg) per day of cannabidiol, the second group received 10 mg/kg per day and the third group received a placebo. The image is in the public domain.

Total seizures reduced by 47 percent for those in the high dose group, by 56 percent for those in the lower dose group and by 30 percent for those in the placebo group. In the high dose group, 49 percent of the participants had their seizures cut in half or more, compared to 44 percent in the low dose group and 26 percent in the placebo group.

All of the groups reported side effects, with 90 percent of the high dose group, 88 percent of the low dose group and 89 percent of the placebo group. The most common side effects were decreased appetite, diarrhea, sleepiness, fever and fatigue. About 25 percent of those in the high dose group had serious side effects, compared to 20 percent of those in the low dose group and 15 percent of those in the placebo group. Only participants in the high dose group stopped taking the drug due to side effects; that number was 7 percent.

“Based on these results, dose increases above 10 mg/kg per day should be carefully considered based on the effectiveness and safety for each individual,” Miller said.

Cannabis-based medicine may reduce seizures for children with difficult-to-treat epilepsy - Neuroscience News

Results from a phase 3 study reveal Cannabidiol (CBD) cuts seizures by almost 50% in children with Dravet syndrome.

neurosciencenews.com

 

[mr peabody]

Synthetic CBD may be a safe treatment for epilepsy

by Catharine Paddock | Medical News Today | May 30 2019

The chemical structure of the synthetic cannabidiol (CBD) is similar to that of the CBD that occurs naturally in the plant Cannabis sativa.

Researchers at the University of California, Davis (UC Davis) and the University of Reading in the United Kingdom have shown that H2CBD can be just as effective as cannabis-derived CBD in treating rats with chemically-induced seizures.

In a Scientific Reports paper on the study, the investigators describe how both compounds reduced the severity and frequency of seizures to the same extent.

"H2CBD is a much safer drug than CBD with no abuse potential and doesn't require the cultivation of hemp," says lead study author Mark Mascal, who is a professor in the Department of Chemistry at UC Davis.

He and his colleagues explain that the use of cannabis as a "treatment of last resort for some cases of refractory epilepsy" was one of the most pressing medical arguments for legalizing marijuana.

Just over 20 years ago scientists discovered the endocannabinoid system, and how its interaction with cannabis compounds affected nerve cells in the brain.

Of the 100 or so cannabis compounds that interact with the endocannabinoid system, there are two major players: delta-9-tetrahydrocannabinol (THC) and its less intoxicating relative, CBD.

Because of the intoxicating effects of THC, medical research on the therapeutic use of the compounds has tended to concentrate on CBD, which does not "cause a high."

The Food and Drug Administration (FDA) have approved an extract of herbal, or plant-derived, CBD for the treatment of certain seizure conditions.

Advantages of synthetic over herbal CBD

However, herbal CBD is not without its disadvantages. The researchers discuss these, and the benefits of an effective synthetic CBD, in their study paper.

A disadvantage of herbal CBD is that because it comes from cannabis, many countries class it as a controlled substance. On the other hand, because H2CBD is synthetic, its use could avoid many of the legal problems that generally arise with trying to use cannabis products.

"Using CBD from cannabis also requires land to grow the cannabis plants, which brings attendant social and environmental concerns," write the authors.

In contrast, chemists can synthesize H2CBD in the laboratory using inexpensive, noncannabis chemicals. They can also purify H2CBD more easily than plant-extracted CBD.

Also, it is not difficult for people to convert herbal CBD into THC, and the chemicals for doing it are readily available. However, as Prof. Mascal explains, "there is no way to convert H2CBD to intoxicating THC."

The team is already planning animal studies to evaluate H2CBD, after which, they intend to move rapidly into clinical trials.

UC Davis have also applied for a provisional patent for the use of H2CBD and derivatives in the treatment of seizures. Prof. Mascal, in the meantime, has set up a private company to press on with developing the drug.

Synthetic CBD may be a safe treatment for seizures

A nonintoxicating, synthetic CBD that is not easy to convert to THC and comprises inexpensive, noncannabis ingredients treated seizures safely in rats.

www.medicalnewstoday.com

 

[mr peabody]

Researchers discover molecules in blood that spike hours before seizures

by Simon Makin | Scientific American | November 2019 Issue

More than 50 million people worldwide have epilepsy, and one of its harshest aspects is its unpredictability. Sufferers rarely know when a seizure will occur.

But molecular biologist Marion Hogg of FutureNeuro, a research institute hosted at the Royal College of Surgeons in Ireland, and her colleagues have found molecules whose levels in the bloodstream differ before and after a seizure. This discovery could lead to a blood test that gauges when seizures are likely to strike, enabling patients to take fast-acting preventive drugs. The study, published in July in the Journal of Clinical Investigation, may even offer clues about epilepsy's causes.

The researchers analyzed plasma samples from the blood of people with epilepsy and found that certain fragments of transfer RNA (tRNA)—a molecule involved in translating RNA into proteins—appear to spike hours before a seizure, then return to a normal level afterward. These fragments form when enzymes cut tRNAs in response to stress, possibly caused by increased brain activity in the run-up to a seizure.

Neurologist Mark Cook of St. Vincent's Hospital in Melbourne, Australia, said "the tRNA fluctuations could reflect the rhythms of biological clocks. In adults with chronic epilepsy, we see cycles running over seven, 28, 40 days,” Cook says. “These patterns control brain excitability, making you more or less liable to seizures.”

The new findings may thus ultimately lead to a better understanding of the causes of epilepsy. “We haven't known what's driving the cycles, but there may be a clue here that there are genes driving the system, generating these fragments, which allow prediction of seizures,” Cook says. “That's very exciting because it tells you something not only about epilepsy but about how the brain works.”

Cook's group previously predicted seizures by monitoring brain activity, but that required invasive surgery. FutureNeuro researchers are working on a seizure-prediction device that uses pinprick blood tests at home, similar to a glucose monitor. The study's analysis needed relatively large amounts of plasma separated from blood—so an immediate challenge is developing a device that works both with small samples and with whole blood. “We anticipate such a device may be available for patients to use in the next five years,” Hogg says.

Advance warnings could make a major difference in patients' lives. “If you had an indication, perhaps you wouldn't go into work, or drive, or go swimming,” Hogg says. And although some epilepsy drugs are fast-acting, most are for long-term management—but nearly a third of patients do not respond to the latter. Cook says that "accurate seizure prediction would encourage drug development for acute use, which could mean fewer side effects as compared with a daily regimen."

Molecules in Blood Spike Hours before Seizures

Researchers measured a predictive increase in transfer RNA in people with epilepsy

www.scientificamerican.com

 

[mr peabody]

Xygel reduces seizures in children with severe epilepsy

by Cheryl Norrie | University of Otago | Oct 2 2019

A cannabidiol gel has been shown to reduce epileptic seizures in children in a clinical trial conducted in New Zealand and Australia.

The gel, which is applied to the skin as a transdermal treatment, was found to reduce the number of focal impaired awareness and convulsive seizures experienced by children with severe epilepsy by up to 58 percent between month two and month six of being treated. At month five, 63 percent of children had a reduction of seizures by at least 50 percent.

The phase II clinical trials of the product, which is being developed by US company Zynerba Pharmaceuticals, took place in Wellington and Melbourne, with a total of 48 children enrolled, 24 in each centre.

Professor Lynette Sadleir, a pediatric neurologist at the University of Otago, Wellington, and Professor Ingrid Scheffer, a pediatric neurologist at the University of Melbourne, were the two principle investigators in the trial.

Professor Sadleir says the product offers new hope for children and adolescents experiencing severe epileptic seizures, who currently have few effective options for treatment.

The phase II clinical trial assessed the product's safety and efficacy in children and adolescents with Developmental and Epileptic Encephalopathies. These are the most difficult to treat epilepsies, and include the conditions Dravet Syndrome and Lennox-Gastaut syndrome. Patients with Developmental and Epileptic Encephalopathy have frequent severe seizures as well as severe cognitive and behavioral impairment.

Professor Sadleir says the gel not only reduced the number of epileptic seizures the children had, but also led to a reported improvement in behavioral and cognitive symptoms. It was also very well tolerated.

"These conditions are the most challenging and poorly controlled of all epilepsy disorders, and have a tremendous impact on the families involved.

"Zygel offers the prospect of these children attending school more frequently, and holds out the hope of a more normal life for their families."

"It can be difficult for children with disabilities to take drugs by mouth, but there is presently no other way to give these children anti-seizure medicines. This gel will be the first anti-seizure medicine that will not have to be given by mouth."

Zynerba says it intends to seek a meeting with the US Food and Drug Administration likely in the first half of next year, to discuss the clinical pathway to approving the product.

Cannabidiol gel reduces seizures in children with severe epilepsy, Australasian trial shows

A cannabidiol gel has been shown to reduce epileptic seizures in children in a clinical trial conducted in New Zealand and Australia.

medicalxpress.com

 

[mr peabody]

Cannabis-based drug for childhood epilepsy approved for use in the UK

by Julia Kollewe | The Guardian | 23 Sep 2019

Plant-derived Epidyolex is first medicine of its kind to be given green light by regulators.

The first cannabis-based medicine for childhood epilepsy is expected to be available soon in the UK and the rest of Europe after its UK manufacturer, GW Pharmaceuticals, received the green light from European authorities.

Cambridge-based GW said the European Medicines Agency (EMA) and the European commission had approved Epidyolex for seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome (LGS) and Dravet syndrome for patients aged two years and older.

The approval means the medicine – a plant-derived, strawberry-flavoured cannabidiol oral solution that is taken twice a day and lacks the “high” associated with cannabis – can be launched across Europe. Up to 50,000 children and young adults in Europe have one of the two syndromes, including about 10,000 in the UK.

GW’s chief operating officer, Chris Tovey, said the company was in discussions with the UK’s National Institute for Health and Care Excellence (Nice) about making the drug available on the NHS. GW is in parallel discussions in other European countries. The drug is already on the market in the US, where about 15,000 young people have been treated.

Tovey said: “The feedback [in the US] has been incredibly positive.” He said he was very optimistic that Nice would agree to fund Epidyolex on the NHS. “We are hoping for a relatively rapid decision from Nice and we are hoping to make it available for UK patients in the next couple of months.”

However, Nice has turned down Sativex, GW’s cannabis-based medicine for multiple sclerosis, on the grounds of its high price, to the dismay of patients and campaigners.

Justin Gover, GW’s chief executive, said: “The approval of Epidyolex marks a significant milestone, offering patients and their families the first in a new class of epilepsy medicines and the first and only EMA-approved CBD [cannabidiol] medicine to treat two severe and life-threatening forms of childhood-onset epilepsy.”

Many patients with LGS or Dravet suffer multiple seizures a day and do not respond to many of the other available treatments. The two syndromes have high mortality rates and many patients die before they reach their early 20s.

When combined with other anti-epileptic therapies, Epidyolex significantly reduced the frequency of seizures in patients with LGS and Dravet syndrome. The most common side effects include sleepiness, decreased appetite, diarrhoea, pyrexia (fever), fatigue and vomiting.

More than 150 patients have already been treated with the medicine in the UK under compassionate use or as part of an early access programme. “We know the families are desperate,” Tovey said.

A change in UK law last year meant medicinal cannabis can be prescribed legally. The change was made after the mother of Billy Caldwell, who has treatment-resistant epilepsy, publicly defied the authorities to bring cannabis oil into the UK.

Doctors have been reluctant to prescribe cannabis-based medicines in the UK, however, because of the lack of clinical trial evidence of its benefits and safety. This could change after the European approval of Epidyolex.

Isabella Brambilla, the chair of the Dravet Syndrome European Federation, said: “We are very happy that patients will now have access to a much-needed new treatment option, and one routed through a rigorous clinical trials programme and licensed by the EMA.”

Elinor Ben-Menachem, professor of neurology and epilepsy at the University of Gothenburg’s Sahlgren Academy, said: “LGS and Dravet syndrome are two of the most severe and difficult-to-treat forms of childhood-onset epilepsy, with few patients achieving adequate seizure control. The EMA approval of Epidyolex will bring hope to patients and families, with the potential to better control seizures and improve quality of life.”

GW has also filed the drug for approval in Switzerland and Israel. It is conducting further clinical trials on the treatment of other forms of epilepsy with the medicine.

Cannabis-based drug for childhood epilepsy approved for use in UK

Plant-derived Epidyolex is first medicine of its kind to be given green light by regulators

www.theguardian.com

 

[mr peabody]

New research could help predict seizures before they happen

Neuroscience News | June 10, 2019

A new study has found a pattern of molecules that appear in the blood before a seizure happens. This discovery may lead to the development of an early warning system, which would enable people with epilepsy to know when they are at risk of having a seizure.

Researchers at FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological Diseases, hosted at RCSI (Royal College of Surgeons in Ireland) led the study, which is published in the current edition of the Journal of Clinical Investigation (JCI).

FutureNeuro and RCSI researchers have discovered molecules in the blood that are higher in people with epilepsy before a seizure happens. These molecules are fragments of transfer RNAs (tRNAs), a chemical closely related to DNA that performs an important role in building proteins within the cell. When cells are stressed, tRNAs are cut into fragments. Higher levels of the fragments in the blood could reflect that brain cells are under stress in the build up to a seizure event.

Using blood samples from people with epilepsy at the Epilepsy Monitoring Unit in Beaumont Hospital, Dublin and in a similar specialist centre in Marburg, Germany, the group found that fragment levels of three tRNAs “spike” in the blood many hours before a seizure.

“People with epilepsy often report that one of the most difficult aspects of living with the disease is never knowing when a seizure will occur,” said Dr Marion Hogg, FutureNeuro investigator, Honorary Lecturer at RCSI, and the study’s lead author.

“The results of this study are very promising. We hope that our tRNA research will be a key first step toward developing an early warning system.”

Approximately 40,000 people in Ireland have epilepsy and one third of those do not respond to current treatments, meaning they continue to experience seizures. The World Health Organisation estimates that more than 50 million people worldwide have epilepsy.

"New technologies to remove the unpredictability of uncontrolled seizures for people with epilepsy are a very real possibility,” said Professor David Henshall, Director of FutureNeuro and Professor of Molecular Physiology and Neuroscience at RCSI who was a co-author on the paper.

“Building on this research we in FutureNeuro hope to develop a test prototype, similar to a blood sugar monitor that can potentially predict when a seizure might occur.”

New research could help predict seizures before they happen - Neuroscience News

Specific transfer RNAs (tRNAs) are associated with epilepsy. The levels of tRNA fragments in blood samples are higher pre-seizure. The findings provide a novel biomarker for the detection of seizures prior to their occurrence.

neurosciencenews.com

 

[mr peabody]

Neuroscientists find they can 'switch off' epileptic seizures*

by Georgetown University | Medical Xpress | Dec 16 2019

A team of neuroscientists at Georgetown University Medical Center have found, in animal models, that they can 'switch off' epileptic seizures. The findings, published online in Proceedings of the National Academy of Sciences (PNAS), provide the first evidence that while different types of seizures start in varied areas of the brain, they all can be controlled by targeting a very small set of neurons in the brain or their tendril-like neuronal axons.

Zeroing in on specific neurons suggests that treatment for epilepsy can be improved, researchers say. For example, "the deep brain stimulation used today could be minutely targeted at the cell body of these neurons or at the areas their axons touch, depending on the type of seizure," says the study's senior investigator, Patrick A. Forcelli, Ph.D., an assistant professor in neuroscience and in pharmacology and physiology at Georgetown.

"We have found a major choke point in epilepsy circuits in rat brains that we believe can be harnessed to disrupt the onset of seizures or to stop their propagation within the brain," he says. "Circuit-based therapy for people will help offset the known side effects that come with drug therapy and other techniques."

According to the CDC, in the U.S., about 3 million adults and almost 500,000 children have epilepsy, making the incidence about 1% of the population, and the fourth most common brain disorder. (Epilepsy is diagnosed when a person has had more than one seizure.)

Seizures occur when nerve cells in the brain misfire. While there are about 30 specific types of seizures, there are two main categories: focal, which start in particular areas of the brain, and generalized, which occur when nerve cells on both sides of the brain misfire. Within this category are tonic-clonic (formerly known as grand mal) convulsive seizure and absence (formerly known as petit mal).

Researchers have known for about 30 years that while inhibiting a certain area of the brain, the substantia nigra pars recticulata (SNpr) can help stop a seizure, the circuits by which the SNpr controls a seizure have remained unclear. The SNpr is a small area deep within the brain. "It is usually thought to be involved in movement and movement disorders," says Forcelli. "We knew targeting SNpr can stop a seizure, but we didn't know how. Neurons in this area have axonal projections that go to many different parts in the brain."

"This study," he says, "is built upon the pioneering work done at GUMC in the 1980s when researchers, led by Karen Gale, Ph.D., built a metaphorical Rand McNally-type atlas of neuronal pathways involved in seizures and epilepsy—these maps have moved forward both basic biology and for pharmacological treatment of epilepsy." The aim of his research is "to make a "Google maps" version with higher resolution and the ability to zoom in on each address, to improve brain stimulation therapy," says Forcelli.

With his team, Forcelli used four models of experimental epilepsy in seizure-prone rats, designed to reflect a different type of seizure (absence, forebrain tonic-clonic, brainstem tonic-clonic, and limbic) seen in human epilepsies.

They were able to stop these seizures by placing light-sensitive ion channels into neurons in the SNpr; when exposed to light, the neurons can be turned on or off. They found that seizures could be turned off by either silencing activity of the SNpr cell bodies or, in some cases, the areas that these neurons project to.

"We can't target therapy if we don't know how the circuits work. Discovering that silencing one area that a SNpr projects to can turn off specific seizures suggests a much more targetable therapy. For example, deep brain stimulation could be aimed at that area," Forcelli said.

"These findings clarify a long-standing question in the field: the role these individual SNpr neural pathways play in the control of seizures."

*From the article here :

Zooming in on brain circuits allows researchers to stop seizure activity

A team of neuroscientists at Georgetown University Medical Center have found, in animal models, that they can "switch off" epileptic seizures. The findings, published online in Proceedings of the National Academy of Sciences (PNAS), provide the first evidence that while different types of...

medicalxpress.com

 

[mr peabody]

Magnolia bark compound could help treat drug-resistant epilepsy

by American Chemical Society | Medical Xpress | 11 Mar 2020

In patients with epilepsy, normal neurological activity becomes disrupted, causing debilitating seizures. Now, researchers report in ACS Chemical Neuroscience that they have found a potential new treatment for this disorder by turning to traditional Chinese medicine. Tests of extracts from plants used in these ancient remedies led the team to one compound, derived from a magnolia tree, that could quell drug-resistant seizures in both fish and mice.

Epilepsy is one of the most common neurological diseases worldwide, and the World Health Organization estimates that about 50 million people have the disorder. Medications are available, but they don't help everyone. Research suggests that about 70% of patients with epilepsy can control it well with medication, leaving many patients without effective treatment. But even when they work, the drugs can cause a range of side effects, from dizziness to mood disruptions. To look for new drug leads that could help even those patients who don't respond to conventional anti-seizure medications, Peter de Witte and colleagues set their sights on plants used in traditional Chinese medicine.

The team collected 14 plants used in traditional Chinese medicine anti-seizure remedies. They then tested the plants' extracts in two types of zebrafish with epileptic-like seizures, one of which could respond to conventional anti-seizure medications, whereas the other type could not. Only extracts from the bark of Magnolia officinalis, a tree native to China, reduced seizure-like behavior in both types of fish. In tests with mice, the researchers found that the magnolia bark's most potent anti-seizure compound, magnolol, reduced the rodents' otherwise drug-resistant seizures. It and similar compounds in magnolia bark could provide a starting point for the development of treatments for resistant epilepsy, according to the researchers.

Magnolia bark compound could someday help treat drug-resistant epilepsy

In patients with epilepsy, normal neurological activity becomes disrupted, causing debilitating seizures. Now, researchers report in ACS Chemical Neuroscience that they have found a potential new treatment for this disorder by turning to traditional Chinese medicine. Tests of extracts from...

medicalxpress.com

 

[mr peabody]

High dose CBD found to alleviate epilepsy by exerting an anticonvulsive effect*

Ke Mao, Chao You, Ding Lei, Heng Zhang

The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD. CBD administration decreased neuronal damage in the hippocampus caused by seizures, resulting in an anticonvulsive effect in the rats with chronic epilepsy.

Our study clearly demonstrates that CBD administration protects against pentylenetetrazole-induced chronic seizures in rats. In addition, the CBD-treated rats exhibited significantly lower astrocytic hyperplasia and neurological defects in the hippocampal area compared with rats in the model control group. The expression of the NMDA1 receptor was selectively suppressed in CBD-treated rats. The rats treated with a high dose of CBD (20 and 50 mg/kg/d) showed a clear inhibitory effects. This is believed to be due to the rapid metabolism of CBD in the peripheral tissues. The blood-brain barrier may also restrict the penetration of CBD into the brain. Therefore, an adequate peripheral dose is required to produce apparent protective effects.

*From the study here:

High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect

 

[mr peabody]

Breakthrough for drug-resistant epilepsy

HEALTH EUROPA | 6 Jan 2020

30% of epilepsy cases are classified as drug-resistant but new research from the University of Alabama suggests there may be new ways to manage drug-resistant epilepsy.

Research surrounding epilepsy is beginning to move away from just targeting the seizures and is beginning to actually focus on their cause. Progress in gene sequencing and animal models are helping scientists and doctors study and sometimes treat the disease.

One of these doctors is Sandipan Pati, M.D. who leads an epilepsy neuromodulation clinic at the University of Alabama, USA. Pati and his colleagues found that people with drug resistant epilepsy also struggle with deleterious neuropsychiatric systems like anxiety, depression, psychosis, and impaired memory.

Pati explained: “Treating these patients can be challenging, and one reason for this is that sometimes seizures can mimic anxiety and panic attacks, or psychosis. Seizure-induced anxiety or psychosis is treated with anti-seizure medications, while ‘pure’ psychosis is treated with antipsychotic medications.:

“This study will be attractive for patients, as anxiety and depression are common problems in epilepsy, and patients get frustrated as they think we are always focused on treating seizures and not depression.”

Study and results

Patients had implanted neurostimulators placed on their brains to control and monitor their epileptic seizures. When a patient felt the onset of a neuropsychiatric episode, they used a magnet that initiates brain recording. The data recorded was then sent to a password protected laptop so physicians could review and help guide treatment and therapies.

The data Pati and his team collected showed whether the neuropsychiatric comorbidity began before, during or after epileptic seizures. Out of the 21 patients in the study, five patients showed significant neurobehavioural comorbidities which overlapped with their seizures, meaning their treatment could be properly adjusted.

The patients in the study all saw their symptoms improve from changes in drug treatment and cognitive therapy to help reduce panic attacks, psychosis and non-epileptic seizures.

Pati highlighted: “The availability of ambulatory electrocorticography provides the opportunity to manage comorbidities in epilepsy that can mimic seizures and contribute to the overall poor quality of life.”

*From the article here :

Research suggests a new breakthrough for drug resistant epilepsy

30% of epilepsy cases are classified as drug resistant but new research suggests there may be new ways to manage drug resistant epilepsy.

www.healtheuropa.eu

 

[mr peabody]

Lamotrigine and psychedelics

SPIRIT PHARAMACIST | 2 Sep 2020

Lamotrigine is a pharmaceutical psychotropic that is classified as both a mood stabilizer and antiepileptic drug. This means that it is primarily indicated in the treatment of bipolar disorder as well as seizures or epilepsy. It works differently than other antidepressants or mood stabilizers and is thought to inhibit the release of the excitatory neurotransmitter glutamate as well as stabilizing neuronal membranes via inhibition of voltage sensitive sodium channels.

Are Lamotrigine users contraindicated from using psychedelics?

Lamotrigine is indicated for bipolar disorder and seizures, which are both conditions that are typically considered to be relatively or absolutely contraindicated when it comes to psychedelic use. However, Lamotrigine is somewhat different than other mood stabilizers for bipolar disorders. While Lamotrigine is categorically classified as a mood stabilizer, it lacks efficacy in the treatment of manic mood states and is primarily used as a niche mood stabilizer for the treatment of depression in persons that have bipolar II disorder. It is also used ‘off label’ at times as an atypical antidepressant (e.g. cyclothymia) or as an adjunct to standard antidepressants.

Bipolar II disorder is predominantly characterized by depression and manic episodes are typically short-lived and relatively mild (hypomania). There is little data to inform if psychedelics could be helpful in persons suffering from depression associated with bipolar II disorder, although there is at least one trial of psilocybin-assisted psychotherapy planned for the population. It is also known at this point that ketamine is helpful in both treatment resistant depression as well as depression associated with bipolar disorder.

Therefore, Lamotrigine use should not automatically disqualify candidacy to undergo a psychedelic therapy and a careful review of the individual’s signs, symptoms, and diagnoses both contemporarily and historically may help in decision-making or identifying contraindications.

How does Lamotrigine interact with psychedelics?

There is little in the way of formal data or information to guide a nuanced understanding of drug interaction between Lamotrigine and psychedelics. However, given Lamotrigine does not strongly interact with serotonergic systems, it is not predicted to interfere with mechanisms of serotonin-based psychedelics (MDMA, psilocybin, LSD, DMT). Furthermore, there is no interaction with monoamine oxidase inhibitors (MAOIs) such as those found in the ayahuasca vine that could plausibly lead to serotonin-related toxicities. Since Lamotrigine does decreases release of glutamate, there is a possibility that it could interfere and diminish the therapeutic effects of ketamine, however this interaction is not well established.

Can I temporarily stop taking Lamotrigine to use psychedelics?

Abrupt discontinuation and temporary suspension of Lamotrigine use is likely a poor idea. This is because Lamotrigine carries special warnings and precautions when it comes to starting and stopping the medication. Lamotrigine is notorious for being able to cause a rare but very severe type of rash called Steven Johnson’s Syndrome or SJS (manifests like a severe burn victim with eyes, mouth, and large body surface area affected). The risk of severe rash seems primarily linked to starting high doses without a slow and careful step up titration procedure as well as starting/stopping high doses of Lamotrigine temporarily. Guidance for prescribers typically recommends restarting from the beginning dose (25mg day) if therapy is interrupted for more than 5 days and considering a lower dose to re-start for treatment interruptions less than 5 days. Concomitant medications may also need factored in and could modify dosing recommendations. In summary, given the complications and risks of interrupting Lamotrigine therapy and the relatively minor interaction potential predicted with serotonergic psychedelics, it is not preferable or necessary to hold Lamotrigine around the time of a psychedelic experience.

How can Lamotrigine be dscontinued safely?

While perhaps not necessary for successful psychedelic therapy, the user may wish to discontinue Lamotrigine as part of their individual therapeutic goals. The prescribing provider should be consulted and in agreement with a plan to taper Lamotrigine before an attempt is made. Various rates of taper have been recommended for Lamotrigine. The most aggressive (excluding emergency discontinuation) of which advocate decreasing the dose by 50% weekly and stopping over a period of at least 2 weeks. Other sources recommend much slower taper schedules and withdrawal of medication over a period of 2-6 months. A longer taper is generally more appropriate when the user has a known sensitivity to dose decreases or there is high concern for mood decompensation or return of seizure activity.

High notes

Lamotrigine is often used for conditions that may present additional risk or are considered to be contraindicated with psychedelics. It likely has little problematic drug interaction with serotonergic psychedelics, although may plausibly interfere with ketamine’s mechanism of action. Due to risks of severe rash when starting or with interruption of Lamotrigine therapy, temporary suspension around the time of psychedelic use is a poor idea. Discontinuation of Lamotrigine in preparation for psychedelic work is generally not necessary yet may be desirable in some persons.

Lamotrigine and Psychedelics — Spirit Pharmacist

Drug interaction summary of lamotrigine with psychedelic substances

www.spiritpharmacist.com

 

[mr peabody]

New analysis indicates that music can help Epilepsy

European College of Neuropsychopharmacology | Neuroscience News | 12·Sep 2020

Listening to Mozart can reduce the frequency of seizures in those with epilepsy, and also reduces abnormal brain activity associated with epilepsy.

A new comprehensive analysis on the effect of Mozart’s music on epilepsy has confirmed that listening to his piano music can reduce the frequency of epilepsy attacks. The results of this comprehensive meta-analysis (a study of studies), which may overturn current scepticism about the effect, are presented at the ECNP congress after recent publication in a peer-reviewed journal.

The idea that listening to Mozart may have beneficial effects on mental health arose from early findings in the 1990s. There have been several studies since, but many involved small numbers of people, or have been of variable quality, leading to mixed evidence overall. This has meant that the “Mozart Effect” has been treated with some scepticism by many clinicians. Now two Italian Researchers, Dr Gianluca Sesso and Dr Federico Sicca from the University of Pisa have conducted a systematic review of works related to the effect of Mozart’s music on epilepsy.

Working according to accepted standard methods for analysing clinical treatment, they looked at 147 published research articles, which they then evaluated according to such things are relevance and quality of the research. This allowed them to select 12 pieces of research which they gathered into 9 separate groups, representing the best available science on the effect of Mozart’s music on epilepsy.

They found that listening to Mozart, especially on a daily basis, led to a significant reduction in epileptic seizures, and also to a reduced frequency of abnormal brain activities in epileptic patients (called interictal epileptiform discharges, which are commonly seen in epileptic patients). These effects occurred after a single listening session and were maintained after a prolonged period of treatment.

Gianluca Sesso said “This isn’t the first such review of the effect of Mozart’s music on epilepsy, but there has been a flow of new research in the last few years, so it was time to stand back and look at the overall picture. The design of the studies varies, for example some people look at a single listening session, others at daily listening sessions, so it’s not easy to form a conclusion."

"Epilepsy is surprisingly common, affecting just under 1 person in a hundred worldwide. This means that it has significant social and personal costs. Mostly it’s treated by drugs, but these drugs don’t work in around 30% of patients, so we need to be open to other therapies: the important thing is that these therapies can be tested and shown to work, and this is what we have shown here.”

The meta-analysis indicates that a period of listening to Mozart can give an average reduction in epileptic seizures ranging from between 31% to 66%, but this varies from person to person and according to the music stimulus used. The original studies on the Mozart Effect used the sonata for 2 pianos, K448, and this has remained the music most used in studies. The K545 piano sonata has also been shown to have an effect.

Dr Sesso said “All cultures have music, so it obviously fulfils some psychological need. The mechanisms of the Mozart Effect are poorly understood. Obviously other music may have similar effects, but it may be that Mozart’s sonatas have distinctive rhythmic structures which are particularly suited to working on epilepsy. This may involve several brain systems, but this would need to be proven."

"This is a review of research, and not original research. One thing it shows is that we need more consistent studies into the effect of music on the mind”

Commenting, Dr Vesta Steibliene, Lithuanian University of Health Sciences, and member of the ECNP Abstract and Poster Committee said:

“There is growing interest in non-invasive brain stimulation techniques in the treatment of neuropsychiatric disorders. This review revealed that Mozart music could be an effective non-invasive method of neurostimulation, reducing the frequency of epileptic seizures, even in hard to treat patients. However, in order to use this method in clinical settings, the exact mechanism of the Mozart music effect on the brain regions should be better understood.”

Is the "Mozart Effect" Real? New Analysis Indicates That Music Can Help Epilepsy - Neuroscience News

Listening to Mozart can reduce the frequency of seizures in those with epilepsy. Exposure to the music of Mozart daily not only significantly reduces seizure frequency, but it also reduces abnormal brain activity associated with epilepsy.

neurosciencenews.com

 

[mr peabody]

Researchers develop wearable device for predicting epileptic seizures

by American Associates, Ben-Gurion University of the Negev | Medical Xpress | 30 Sep 2020

Ben-Gurion University researchers have developed Epiness, a new, first of its kind device for detecting and predicting epileptic seizures based on proprietary machine-learning algorithms. The wearable device can generate an advanced warning about an upcoming seizure that will be sent to a smartphone up to an hour prior to its onset. The system was out-licensed for further development and commercialization to NeuroHelp, a startup company that was recently founded by BGN Technologies, the technology transfer company of BGU and Dr. Oren Shriki, of BGU's Department of Cognitive and Brain Sciences and NeuroHelp's scientific founder.

Epilepsy is a highly pervasive, and at times debilitating neural disease. Up to 30% of patients do not adequately respond to anti-epileptic drugs and live under constant fear of impending seizures. For such patients, a viable seizure prediction device could offer a substantial improvement in quality of life, enabling them to avoid seizure-related injuries. Current seizure alarm devices can detect a seizure in real time but are unable to provide advanced warnings of impending seizures.

Epiness is a seizure prediction and detection device that is based on a new, ground-breaking combination of EEG-based monitoring of brain activity together with proprietary machine-learning algorithms. The device combines a wearable EEG device with state-of-the-art software that minimizes the number of necessary EEG electrodes and optimizes electrode placement on the scalp. The sophisticated machine-learning algorithms are designed to filter noise that is not related to brain activity, extract informative measures of the underlying brain dynamics, and distinguish between brain activity before an expected epileptic seizure and brain activity when a seizure is not expected to occur.

"Epileptic seizures expose epilepsy patients to various preventable hazards, including falls, burns and other injuries," said Dr. Oren Shriki. "Unfortunately, currently there are no seizure-predicting devices that can alert patients and allow them to prepare for upcoming seizures. We are therefore very excited that the machine-learning algorithms that we developed enable accurate prediction of impending seizures up to one hour prior to their occurrence. Since we have also shown that our algorithms enable a significant reduction in the number of necessary EEG electrodes, the device we are developing is both accurate and user friendly. We are currently developing a prototype that will be assessed in clinical trials later this year."

"Epilepsy that is not adequately controlled by medication is prevalent, amounting up to 30% of epilepsy cases, and therefore, an accurate, easy to use seizure predicting device is a highly necessary unmet medical need," said Dr. Hadar Ron, Chairperson of NeuroHelp. "Current seizure alert devices can detect seizures while they are happening, and most of them depend on changes in movement, such as muscle spasms or falls. Epiness is unique in that it can predict an upcoming seizure and allow the patients and their caretakers to take precautionary actions and prevent injuries. It is also the only device that is based on brain activity rather than muscle movements or heart rate. We are confident that Epiness will be a valuable tool in the management of drug-resistant epilepsy."

Josh Peleg, CEO of BGN Technologies, the technology transfer company of BGU, added, "NeuroHelp, a spin-off of BGN Technologies, was recently founded as part of BGU's Oazis accelerator, formed by BGU's Yazamut360 Entrepreneurship Center, to further develop and commercialize their innovative solution for the benefit of people suffering from epilepsy. Earlier this month, NeuroHelp won first prize in the SiliconNegev startup competition, an important recognition of the outstanding potential of this technology, which is based on a unique combination of brain research and artificial intelligence knowhow developed at Dr. Shriki's laboratory."

The new algorithm was developed and tested using EEG data from a large dataset of people with epilepsy that were monitored for several days prior to surgery. The patient data were divided into short segments that were either preictal (pre-seizure) or inter-ictal. Several machine learning algorithms with differing complexities were trained on pre-allocated training data (comprising 80% of the initial EEG data), and their prediction performance as well as electrode-dependent performance was assessed on the remaining 20% of the data. The algorithm with the best prediction performance reached a 97% level of accuracy, with near optimal performance maintained (95 percent) even with relatively few electrodes.

Researchers develop wearable device for predicting epileptic seizures

Ben-Gurion University of the Negev researchers have developed Epiness, a new, first of its kind device for detecting and predicting epileptic seizures based on proprietary machine-learning algorithms. The wearable device can generate an advanced warning about an upcoming seizure that will be...

medicalxpress.com

 

[mr peabody]

Antiepileptic drug VPA linked with increased risk of neurodevelopmental disorders in offspring

Genetic Engineering & Biotechnology News | 24 Oct 2020

The results of a study headed by researchers at the French National Agency for Medicines and Health Products Safety (ANSM), indicate that children born to mothers who took the antiepileptic drug sodium valproate (VPA) during pregnancy may have a four- to fivefold increased risk of developing neurodevelopmental disorders in early childhood. Rosemary Dray-Spira, PhD, and colleagues used anonymized medical records from more than 1.5 million children born in France, to investigate the incidence of neurodevelopmental disorders (NDs) in young children exposed to antiepileptic drugs (AEDs). Their results suggested that the highest risks were associated with VPA, and that the risk of neurodevelopmental disorders were much lower in children whose mothers took other types of AED.

Reporting on their findings in Scientific Reports, “Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France,” the authors concluded. “The results for VPA confirm published data concerning both the level of increased risk NDs associated with exposure during pregnancy, the nature of these disorders and the dose-dependent nature of this risk.”

Epilepsy is one of the most common conditions affecting women of reproductive age, and most need antiepileptic drugs to avoid the harmful effects of uncontrolled seizures on themselves and on their children, the authors wrote. However, in utero AED exposure has been linked with congenital malformations of varying degrees of severity, and with neurodevelopmental disorders, they continued. In utero exposure to VAP, in particular, is associated with poorer educational attainment, poorer cognitive skills, and various neurodevelopmental disorders, including motor disorders, attention-deficit/hyperactivity disorder and autism spectrum disorders.

“These disorders may affect 30 to 40% of exposed children, and their frequency increases with the dose of VPA administered to the mother,” the scientists wrote. Information on the risks is limited, however. “Although a number of studies have been conducted on this topic, it is difficult to draw firm conclusions given the variety of methods and outcomes considered, related to cognitive skills (e.g. IQ or language skills), NDs (e.g. autism spectrum disorders, or attention-deficit/hyperactivity disorder) or school performance … previous studies have failed to determine whether the risk differs according to the period of exposure during pregnancy. Data concerning other AEDs are heterogeneous and insufficient to allow any definitive conclusions concerning the risk of NDs.”

For their studies, the team turned to the French National Health Data System, and followed infants who were born between January 2011 and December 2014, from birth up until December 2016. Mean follow-up was 4 years. The cohort included 1,721,990 children. Of their mothers, 11,549 had been treated with one of several common antiepileptic drugs during pregnancy, and 15,458 (1 percent) of children were identified as having neurodevelopmental disorders by the end of 2016. Of those AED-exposed children, 50 of the 991 (5 percent) who were exposed to VPA in utero were diagnosed with neurodevelopmental disorders in their first five years, compared with 15,270 of 1,710,441 children (1 percent) who hadn’t been exposed to any antiepileptic drugs.

Overall, children exposed to sodium valproate before birth had a 5 times higher likelihood of intellectual disability, a 5 times higher likelihood of language, learning and motor disorders and a 4.6 times higher risk of autism spectrum disorders, than children who hadn’t been exposed to AEDs. Increased risk was not observed in children exposed to sodium valproate during the first trimester only, and the risk was lower among children exposed to lower doses of the drug, than it was among those exposed to higher VPA doses.

Children born to mothers treated with the antiepileptic drugs lamotrigine, carbamazepine and pregabalin were 2 times more at risk of developing neurodevelopmental disorders, respectively. No increased risk of neurodevelopmental disorders was observed in children born to mothers treated with the antiepileptic drugs clonazepam, gabapentin, levetiracetam or oxcarbazepine.

The scientists suggested that their results provide new information on the risks of early NDs associated with in utero exposure to VPA and to other AEDs. “ … it shows a four to fivefold higher risk of early NDs following exposure to VPA, more specifically concerning pervasive developmental disorders, mental retardation and disorders of psychological development,” they wrote. “Exposure to VPA, which was found to have a dose–response relationship with occurrence of NDs, also had a different impact according to the period of exposure: children exposed during the second and/or third trimesters of pregnancy had a markedly increased risk of early NDs, unlike children exposed to VPA only during the first trimester.”

The study also provides new insights into the ND risks to offspring of in utero exposure to other AEDs. “Almost no data concerning the risks of NDs associated with the other AEDs considered in our study are available in the literature,” the team noted. “The results of the present study do not suggest an increased risk of a diagnosis of NDs associated with exposure to clonazepam, gabapentin, levetiracetam or oxcarbazepine during pregnancy. However, our finding of an increased risk of mental retardation and utilization of orthoptic services among children exposed to pregabalin constitutes a signal that needs to be further investigated.”

Maternal Use of Antiepileptic Drug Linked with Increased Risk of Neurodevelopmental Disorders in Offspring

Results of a study in France suggested that highest, dose-dependent risks of neurodevelopmental disorders were associated with maternal use of sodium valproate.

www.genengnews.com

 

[mr peabody]

D-serine could protect against epileptic seizures

by Hannah Balfour | Drug Target Review | 15 Oct 2020

A team of researchers has found that an amino acid produced by the brain, called D-serine, could play a crucial role in preventing temporal lobe epileptic seizures.

Scientist identified the mechanism through which temporal lobe epileptic seizures are sparked and that D-serine can interfere with this process, preventing seizures.

The temporal lobe processes sensory information, creates memories, comprehends language and controls emotion. Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults, often occurring as the result of a head trauma such as a concussion and cannot be improved with currently available anti-epileptic medications. Temporal lobe epileptic seizures can cause neuronal loss of function and neuronal death, resulting in lasting damage.

In their research, Sanjay Kumar, an associate professor in the Florida State University College of Medicine’s Department of Biomedical Sciences, and his team are attempting to find effective therapies for TLE. In their latest study they found that a mechanism responsible for triggering epileptic seizures could be inhibited by an amino acid known as D-serine. As a result, it can also prevent the death of neural cells that accompanies seizures.

“A hallmark of TLE is the loss of a vulnerable population of neurons in a particular brain region called the entorhinal area,” Kumar said. “We are trying to understand why neurons die in this brain region in the first place. From there, is there anything that we can do to stop these neurons from dying? It is a very fundamental question.”

To understand TLE pathophysiology the Kumar lab studies receptors located in the junctions between two or more communicating neurons, which enable neurons to pass signals between them. They discovered in their study a new type of receptor, dubbed the “FSU receptor”, in the entorhinal cortex of the brain. The FSU receptor is a potential target for TLE therapies.

“What is striking about this receptor is that it is highly calcium-permeable, which is what we believe underlies the hyperexcitability and the damage to neurons in this region,” Kumar said.

According to the researchers, when FSU receptors allow too much calcium to enter neurons, TLE patients experience epileptic seizures as neurons become overstimulated by the influx. This hyperexcitability is what causes neurons to die, a process known as excitotoxicity.

The research team also found that the amino acid D-serine blocks these receptors, preventing the calcium influx and the resulting seizure activity and excitotoxicity. Kumar commented: “What is unique about D-serine, unlike any other drugs that are out there, is that D-serine is made in the brain itself, so it is well-tolerated… Many medications that deal with treating TLE are not well-tolerated, but given that this is made in the brain, it works very well.”

With assistance from Michael Roper’s lab in the FSU Department of Chemistry and Biochemistry, the research team found that D-serine levels were depleted in epileptic animals, indicating that TLE patients may not produce sufficient amounts of D-serine. Kumar explained: “The loss of D-serine essentially removes the brakes on these neurons, making them hyperexcitable. Then, the calcium comes in and causes excitotoxicity, which is the reason why neurons die. So, if we provide the brakes – if we provide D-serine – then you do not get that loss of neurons.”

According to their research, neuroinflammation is the cause for diminished D-serine levels in the entorhinal cortex of epileptics. D-serine is typically produced by glial cells, but neuroinflammation experienced as part of TLE causes cellular and molecular changes in the brain that can prevent it from being produced.

The team said their next step is to explore potential administration techniques for D-serine. Kumar explained: “We have to find creative ways to administer D-serine to that particular region of the human brain. Getting it to that right place is the challenge. We have to look at what effect it has when administered locally to that region of the brain compared to systemically through an IV, for example.”

Kumar concluded: “There are some very interesting questions to ask and solve. The important thing is that we have outlined the basic bread-and-butter mechanisms of why D-serine works. What we have established is the discovery of the receptors, discovery of the antagonist for these receptors (D-serine), how it works and how to prevent the emergence of TLE. The mechanisms and pathophysiology are as relevant to the animal model as they are to human beings and that is where the excitement lies.”

D-serine could protect against epileptic seizures

Scientist identified the mechanism through which temporal lobe epileptic seizures are sparked and that D-serine can prevent seizures.

www.drugtargetreview.com

 

[mr peabody]

CBD does not appear to cause adverse cognitive changes in children with treatment-resistant epilepsy

by Eric Dolan | PsyPost | 17 Jan 2021

Cannabidiol (CBD), a compound derived from the cannabis plant, does not impair cognitive functioning when used in the treatment of children with intractable epilepsy, according to new research published in the journal Epilepsy & Behavior.

Previous research has found that CBD can reduce the number of seizures in patients with epilepsy. But the potential cognitive side-effects of long-term CBD use had not been examined in pediatric populations.

“This topic was interesting to me because it provided me with an opportunity to participate in a project that potentially offered some hope to children who had seizures who had not previously responded to multiple other medications,” said researcher Matthew Thompson, a clinical neuropsychologist at Children’s of Alabama hospital.

“Also, most of these children were not good candidates for surgical intervention, so CBD had the potential to offer some relief in terms of seizure control for many children. But we wanted to make sure there were no adverse cognitive consequences of this new medication.”

The study examined 38 participants between the ages of 3 and 19 years with treatment-resistant epilepsy who were enrolled in an open-label study of a pharmaceutical CBD formulation.

“The CBD product we used (Epidiolex) was a pharmaceutical-grade product that is available only by prescription. It is important for readers to know that this wasn’t the product you might purchase over the counter; instead, it is produced by a regulated pharmaceutical company, such that we know the precise concentration of CBD,” Thompson explained.

Prior to initiating CBD and one year later, 14 participants completed a computerized test of cognitive abilities that assessed attention/working memory, executive function, episodic memory, and language. A primary caregiver completed a behavior assessment instrument for the other 24 participants, who were not capable of completing computerized testing because of the magnitude of their impairment.

After one year of continuous CBD use, the researchers observed no significant changes in the cognitive performance or functional adaptive status of the participants.

“I believe the most important take away from this study is that CBD does not appear to cause any adverse cognitive changes in most children who have this medication prescribed for intractable epilepsy,” Thompson told PsyPost.

“We still need more information on a larger group of higher functioning children. Many of the children in this study were very impaired from a cognitive perspective, and this level of impairment made it difficult to detect changes in cognitive function; thus we had to rely on parent report of daily functioning, which has limitations.”

The study, “Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy,“ was authored by Matthew D. Thompson, Roy C. Martin, Leslie P. Grayson, Steve B. Ampah, Gary Cutter, Jerzy P. Szaflarski, and E. Martina Bebin.

CBD does not appear to cause adverse cognitive changes in children with treatment-resistant epilepsy

Cannabidiol (CBD), a compound derived from the cannabis plant, does not impair cognitive functioning when used in the treatment of children with ...

www.psypost.org

 

[mr peabody]

When the hippocampus was stimulated, epileptic seizures failed to occur.

Deep Brain Stimulation prevents epileptic seizures

University of Freiburg | Neuroscience News | 19 Feb 2021

Epileptic activity originating from one or more diseased brain regions in the temporal lobe is difficult to contain. Many patients with so-called temporal lobe epilepsy often do not respond to treatment with anti-epileptic drugs, and the affected brain areas must therefore be surgically removed. Unfortunately, this procedure only gives seizure freedom to about one third of patients, so the development of alternative therapeutic approaches is of great importance.

Scientists led by neurobiologist Dr. Carola Haas, head of the research group at the Department of Neurosurgery at Medical Center – University of Freiburg and the BrainLinks-BrainTools research center, have investigated a new therapeutic approach to prevent epileptic seizures in temporal lobe epilepsy.

They showed in mice that low-frequency stimulation of specific brain areas could completely stop epileptic activity. Instead of using electric current, the researchers stimulated the cells with light. To do this, they had previously introduced a light-sensitive molecule into the cells that allows particularly precise stimulation.

They published the results in December 2020 in the scientific journal elife.

“As soon as we stimulated the brain region with a frequency of one hertz, the epileptic seizures disappeared. This effect was stable over several weeks,” Haas says. Habituation, which can occur with drug therapy, did not take place. The brain region was stimulated for one hour daily.

Circuits and cells identified

In temporal lobe epilepsy, the hippocampus is often pathologically altered and usually represents the so-called focus of epileptic activity. Previous studies have used precise genetic labeling techniques to map the fiber system and its synaptic contacts between the temporal lobe and hippocampus, which are typically preserved in temporal lobe epilepsy.

The researchers used this fiber system to manipulate hippocampal activity in a specific and temporally precise manner using light-dependent proteins. Measuring brain waves showed that rhythmic activation of the diseased hippocampus at a low frequency of one hertz suppressed epileptic activity and prevented it from spreading.

Haas and her colleagues demonstrated that the anti-epileptic effect is largely due to the repeated activation of surviving granule cells in the seizure focus. Single cell studies confirmed the assumption that the granule cells are less excitable due to the stimulation, making the epileptic seizure less likely to spread.

“It’s also possible that we have a widespread network effect because the stimulation can spread through the hippocampal circuitry,” Haas said.

In the future, the team, along with the medical physics department at the Medical Center – University of Freiburg, would like to use magnetic resonance imaging to observe the entire brain during stimulation. This technique could be used to identify additional brain regions that are affected by the stimulation. Corresponding findings on these could provide information on how they are connected and what further consequences stimulation has.

Deep Brain Stimulation Prevents Epileptic Seizures - Neuroscience News

Hippocampal deep brain stimulation prevented seizures in mouse models of temporal lobe epilepsy.

neurosciencenews.com

 

[mr peabody]

The new model is able to accurately predict whether a seizure may happen
within one hour, allowing the patient to take the necessary intervention.

Early-warning for seizures could be a game-changer for those with epilepsy*

Viterbi School of Engineering & Keck Medicine of USC | Neuroscience News | 26 Feb 26 2021

A new mathematical algorithm examines data from EEG and brain implants to learn each epilepsy patient’s unique brain pattern signatures. The system can predict the onset of a seizure within an hour, allowing the patient to take necessary interventions.

Epilepsy is one of the most common neurological conditions, affecting more than 65 million worldwide. For those dealing with epilepsy, the advent of a seizure can feel like a ticking time bomb. It could happen at any time or any place, potentially posing a fatal risk when a seizure strikes during risky situations, such as while driving.

A research team at USC Viterbi School of Engineering and Keck Medicine of USC is tackling this dangerous problem with a powerful new seizure predicting mathematical model that will give epilepsy patients an accurate warning five minutes to one hour before they are likely to experience a seizure, offering enhanced freedom for the patient and cutting the need for medical intervention.

The research, published in the Journal of Neural Engineering, is led by corresponding authors Dong Song, research associate professor of biomedical engineering at USC Viterbi School of Engineering and Pen-Ning Yu, former PhD researcher in Song’s lab, in collaboration with Charles Liu, professor of clinical neurological surgery and director of the USC Neurorestoration Center. The other authors are David Packard Chair in Engineering and professor of biomedical engineering, Ted Berger, and medical director of the USC Comprehensive Epilepsy Program at the Keck Medical Center, Christianne Heck.

The mathematical model works by learning from large amounts of brain signal data collected from an electrical implant in the patient. Liu and his team have already been working with epilepsy patients with implantable devices, which are able to offer ongoing real-time monitoring of the brain’s electrical signals in the same way that an electroencephalogram (EEG) uses external electrodes to measure signals. The new mathematical model can take this data and learn each patient’s unique brain signals, looking out for precursors, or patterns of brain activity that show a “pre-ictal” state, in which a patient is at risk of seizure onset.

Song said the new model is able to accurately predict whether a seizure may happen within one hour, allowing the patient to take the necessary intervention.

“For example, it could be as simple as just alerting the patient their seizure is coming the next hour, so they shouldn’t drive their car right now, or they should take their medicine, or they should go and sit down” Song said. “Or ideally in future we can detect seizure signals and then send electrical stimulation through an implantable device to the brain to prevent the seizure from happening. The discovery would have major positive implications for public health, given epilepsy treatment had been severely impacted in the past year by the pandemic."

“This is hopefully, going to change the way we deal with epilepsy going forward and it’s driven by the needs that have been in place for a long time, but have been highlighted and accelerated by COVID,” said Charles Liu.

"Currently, patients with medically intractable epilepsy-epilepsy that cannot be controlled with medication-are admitted electively to the hospital for video EEG monitoring. With the advent of COVID, these elective admissions completely halted and epilepsy programs across the country ground to a halt over the past year. This highlights the need for a new workflow by which EEG recordings from scalp or intradural electrodes can be acquired at home and analyzed computationally."

“So we need to create a new workflow by which, instead of bringing patients to the ICU, we take the recordings from their home and use the computation models to do everything they would have done in the hospital,” Liu said. “Not only can you manage patients using physical distancing, you can also scale in a way that only technology allows. Computation can analyze thousands of pages of data at once, whereas a single neurologist cannot.”

How the seizure prediction model works

Song said the new model was different to previous seizure prediction models in that it extracts both linear and non-linear information from the patient’s brain signals.

“Linear is the simple feature. If you understand the parts, you can understand the whole,” Song said. “Whereas the non-linear feature means that even if you understand the parts, when you scale up it has some emergent properties that cannot be explained.”

“For some patients, linear features are more important and for other patients, non-linear features are more important,” Song said.

Song said that while other models predict brain activity over a short time scale, a matter of milliseconds, his team’s model examined an extended time scale.

“The brain is a multi-temporal scale device so we need to understand what happens not just in the short term, but many more steps in the future. The model is also unique in that it is patient-specific-it extracts the information that is significant for each individual patient. Because every brain is very different in terms of the signals that indicate a 'pre-ictal' state,” Song said.

He said that "the model is also unique in that it is patient-specific-it extracts the information that is significant for each individual patient. Because every brain is very different in terms of the signals that indicate a 'pre-ictal' state."

“Patients are all different from each other, so in order to accurately predict seizures, we need to record signals, we need to look at a lot of different features and we need to have an algorithm to select the most important feature for prediction,” Song said.

“I can’t tell you how exciting, this is. At USC we’ve been very interested in trying to create tools that enhance the public health dimension of these diseases that we’re treating, and it’s really difficult,” Liu said

“Epileptologists are still relatively few in number in many parts of our country and world. While they can identify many subtle features on EEG, the kinds of models that Song can create can identify additional features at a massive scale necessary to help the millions of patients affected by epilepsy in our region and worldwide,” Liu said.

Heck, who is also co-director for the USC Neurorestoration Center, said that there are two important issues to the clinical relevance of this technology.

“One is that a majority of patients who suffer from epilepsy live with fear and anxiety about their next seizure which may strike like lightening in the most inopportune moment, perhaps while driving, or just walking in public. An ample warning provides a critical ‘get safe’ opportunity,” Heck said. “The second relevant issue clinically is that we have brain implants, smart devices, that this engineered technology can enhance, giving greater hope for efficacy of our existing therapies.”

*From the article here :

Early-Warning for Seizures Could Be a Game-Changer for Epilepsy Patients - Neuroscience News

A new mathematical algorithm examines data from EEG and brain implants to learn each epilepsy patient's unique brain pattern signatures. The system can predict the onset of a seizure within an hour, allowing the patient to take necessary interventions.

neurosciencenews.com